Glucagon has opposite physiological functions to those of insulin and a balance between the two hormones is required for glucose homeostasis. In the diabetic state where insulin is ineffective or absent, the continued presence of glucagon, occasionally at elevated levels, is an important aetiological factor. The goal of the proposed research is to develop a chemically modified form of glucagon which will be effective in blocking the action of the native hormone at its target organs. Two approaches will be used to do this. In one, the hormone will be modified in such a way as to interfere with its ability to activate adenylate cyclase and glucose production in hepatocytes but not with its ability to bind to the hormone receptor. It will thus act as a glucagon antagonist. The other approach is to prepare a chemically modified form of glucagon which will act as a photo-affinity label. This derivative will have a high affinity for and a slow rate of dissociation from the glucagon receptor, thus enabling one to specifically modify and identify the receptor site for glucagon. The chemically altered receptor will be blocked from further interaction with the native hormone. This work will lead to the development of an antagonist to glucagon action. It will present the possibility of a new approach to diabetes therapy through the specific blocking of the action of glucagon at its target organ. It will also result in a better understanding of the mechanisms of action of glucagon and of hormone-receptor interaction.